This proposal describes a 5 year training program for the candidate's development as a Physician-Scientist and successful Independent Investigator. The candidate has completed Residency training in Radiation Oncology at the University of Pennsylvania and has passed his Radiation Oncology Board-Certification exams. He will now expand his scientific skills through a customized integration of institutional resources and mentored experiences. The candidate has a background in cell and molecular biology, but will greatly benefit from additional training in radiation biology, radiation oncology, molecular imaging, high-throughput screening, and experimental therapeutics. The University of Pennsylvania and the Department of Radiation Oncology have committed to fully support the proposed career development program and provide an ideal setting for training Physician-Scientists by acquiring and maintaining outstanding resources and nurturing a collaborative environment. Such an environment maximizes the potential for the candidate to construct a successful independently-funded academic career. The project described therefore takes advantage of the exceptional resources available at the Abramson Cancer Center and the University of Pennsylvania. Co-leaders of the Abramson Cancer Center's Radiation Biology &Imaging Program, Dr. Constantinos Koumenis, Associate Professor of Radiation Oncology and Dr. Stephen M. Hahn, Henry K. Pancoast Professor and Chair of Radiation Oncology will mentor the candidate's scientific and career development. Together, Drs. Koumenis and Hahn have formalized a research plan with a career development strategy augmented by a strong formal program that includes regular lab meetings, seminars, journal clubs and didactic training as well as a process of regularly scheduled review to ensure progress. The proposed research will focus on delivering molecular targeted therapy for Glioblastoma Multiforme (GBM) via the novel strategic integration of ER stress and the extrinsic pathway of apoptosis. Despite the recently demonstrated efficacy of temozolomide (Temodar) in treating glioblastoma multiforme (GBM), it remains an incurable and devastating disease. New therapeutic approaches are desperately needed. The candidate has identified a novel mechanistic model of therapy that integrates the ER stress and death receptor pathways in human GBM cells to induce apoptosis. Effective pre-clinical validation of this integrated therapeutic strategy could serve as a model for development of ER stress/apoptosis-based targeted therapy against cancer in general. This project aligns well with the immediate career goal of applying mechanistic and high-throughput screening approaches to identify novel targets for cancer therapy, and the long-term career goal of translating these findings into effective targeted therapy for high-grade brain tumors. The mentorship of Drs. Constantinos Koumenis and Stephen Hahn, the unique resources and collaborative nature of the Abramson Cancer Center/University of Pennsylvania, and the translational clinical activities in the Roberts Proton Therapy Center/Perelman Center for Advanced Medicine/Translational Research Center together provide an exceptional environment to support the successful execution of the research project and the career development of the candidate. Furthermore, the program incorporates unique external scientific resources and expertise from the Wistar Institute and Johns Hopkins University to enhance the candidate's research and career development. Through the completion of the program described, the candidate will proceed to full independence with the expectation of successful achievement of R01 funding within five years. PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme is the most common primary brain cancer in adults and is a lethal and devastating tumor. This research focuses on developing and testing an innovative strategy to molecularly integrate two biological pathways leading to cell death. Results of these studies will ultimately benefit public health by potentially improving therapies against these tumors and cancer in general.